Impact of heme and heme degradation products on acute kidney injury associated with Shiga toxin 2-induced hemolytic-uremic syndrome

血红素和血红素降解产物对志贺毒素2诱导的溶血尿毒症综合征相关急性肾损伤的影响

• 批准号: 273371358
• 负责人: Professorin Dr. Sina Maren Coldewey, Ph.D.
• 金额: --
• 依托单位: Klinik für Anästhesiologie und Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/273371358?language=en
• 关键词: Impact; heme; degradation; products; acute

The hemolytic-uremic syndrome (HUS) is a serious extra-intestinal complication of infections with enterohemorrhagic Escherichia coli (EHEC). Bacterial Shiga toxins (Stx), in particular Stx2, play an essential role in HUS pathogenesis by triggering thrombotic microangiopathy and subsequently the typical triad of symptoms of hemolytic anemia, thrombocytopenia and acute kidney injury. Recently, the central role of extracellular "free" heme as a perpetuating factor in lifethreatening infections, even with a very moderate degree of hemolysis, has been acknowledged. However, the impact of hemolysis, "free" heme and heme degradation products (HHDPs) as well as hemoglobin- and heme-neutralizing proteins and heme-catabolizing enzymes (heme oxygenase 1, HO1) on the degree of acute kidney injury in HUS, as a paradigm for hemolytic anemia with concomitant inflammation, requires investigation. In striking contrast to other forms of hemolytic anemia, a parallel decrease in erythropoietin (EPO) serum levels has been described in HUS patients. This might be due to either inflammation via inhibition of EPO gene expression or a HUS characteristic direct damage to the kidneys with concomitant renal anemia. The pleiotropic hormone EPO is known to have organ protective properties, which are independent of its well-established hematopoietic effects. There is increasing evidence that the tissue-protective effects of EPO are mediated by a heterocomplex of the erythropoietin receptor and the b-common receptor (bcR) that is pharmacologically distinct from the erythropoietin receptor homodimer conveying erythropoiesis. Thus, a critical imbalance between hemolysis/heme-dependent injury and EPO/bcR-dependent protection might aggravate renal dysfunction in HUS. Understanding this imbalance carries the potential for novel therapeutic strategies. In the proposed subproject we aim to establish the role of hemolysis/extracellular heme and the EPO/bcR signaling axis in the development of HUS-associated acute kidney injury. In a translational approach we will specifically investigate (i) the role of hemolysis and formation of HHDPs (ii) the impact of hemoglobin- and heme-scavenging proteins (iii) the impact of HO1, and (iv) the impact of EPO and the potential bcR-mediated tissue protective effects of EPO on renal dysfunction and injury in HUS. We will address these objectives systematically in a model of Stx2-mediated experimental HUS by employing mice deficient for haptoglobin, hemopexin, HO1 or bcR. These mechanistic murine studies will be complemented by quantification of HHDPs and EPO in serum samples from HUS patients and by correlating the results to the degree/outcome of renal dysfunction in these patients. The proposed studies will enable us to characterize the impact of hemolysis/heme and the EPO/bcR signaling axis in the pathogenesis of Stx2 propagated renal dysfunction and injury, a significant risk factor for end-stage kidney disease.

溶血性尿毒综合征（HUS）是肠出血性大肠杆菌（EHEC）感染的一种严重肠外并发症。细菌滋贺毒素（Stx），特别是Stx 2，通过触发血栓性微血管病以及随后的溶血性贫血、血小板减少症和急性肾损伤的典型三联征在HUS发病机制中起重要作用。最近，细胞外“游离”血红素作为危及生命的感染中的永久因子的中心作用，即使具有非常中度的溶血，也已被承认。然而，溶血、“游离”血红素和血红素降解产物（HHDPs）以及血红蛋白和血红素中和蛋白和血红素分解代谢酶（血红素加氧酶1，HO 1）对HUS急性肾损伤程度的影响，作为溶血性贫血伴发炎症的范例，需要调查。与其他形式的溶血性贫血形成鲜明对比的是，在HUS患者中已经描述了红细胞生成素（EPO）血清水平的平行降低。这可能是由于通过抑制EPO基因表达引起的炎症或HUS特征对肾脏的直接损伤伴发肾性贫血。已知多效性激素EPO具有器官保护特性，其独立于其公认的造血作用。越来越多的证据表明，EPO的组织保护作用是由促红细胞生成素受体和b-common受体（bcR）的异源复合物介导的，bcR与输送红细胞生成的促红细胞生成素受体同型二聚体截然不同。因此，溶血/血红素依赖性损伤和EPO/bcR依赖性保护之间的严重失衡可能会加重HUS的肾功能障碍。了解这种不平衡带来了新的治疗策略的潜力。在拟议的子项目中，我们的目标是建立溶血/细胞外血红素和EPO/bcR信号转导轴在HUS相关急性肾损伤的发展中的作用。在翻译方法中，我们将专门研究（i）溶血和HHDPs形成的作用（ii）血红蛋白和血红素清除蛋白的影响（iii）HO 1的影响，以及（iv）EPO的影响和EPO对HUS肾功能障碍和损伤的潜在bcR介导的组织保护作用。我们将通过采用结合珠蛋白、血红素结合蛋白、HO 1或bcR缺陷的小鼠，在Stx 2介导的实验性HUS模型中系统地解决这些目标。这些机制性鼠研究将通过对来自HUS患者的血清样品中的HHDP和EPO进行定量以及通过将结果与这些患者中的肾功能障碍的程度/结果相关联来补充。拟议的研究将使我们能够表征溶血/血红素和EPO/bcR信号传导轴在Stx 2传播性肾功能不全和损伤（终末期肾病的重要风险因素）的发病机制中的影响。